Legionnaires' disease is a major and widespread medical problem. Its incidence is much higher than previously realized and it is frequently fatal even with treatment. To formulate a rational strategy for prevention (including vaccination) and treatment, it is extremely important to define the immunobiology of the causative agent, Legionella pneumophila, and the roles of humoral and cellular immunity in host defense against it. My studies have begun to do this. They have shown (1) that L. pneumophila multiples intracellularly in human monocytes and that the bacterium is a facultative intracellular parasite; (2) that virulent L. pneumophila resists killing by complement and by human polymorphonuclear leukocytes and monocytes even in the presence of anti-L. pneumophila antibody and complement; and (3) that anti-L pneumophila antibody does not inhibit the intracellular multiplication of L. pneumophila. These studies and the ones proposed here represent the first systematic attempt to explore and understand the phagocyte-parasite relationship in Legionnaires' disease. Such studies should not only enhance our understanding of Legionnaires' disease but they should also contribute to our general understanding of intracellular parasitism and cell-mediated immunity; the L. pneumophila-monocyte in vitro model has proved to be an excellent one for the study of these important immunologic phenomena, providing several important advantages over all previously studied models. Moreover, the model allows study of human cell-mediated immunity, about which little is known. Specifically, I seek to (1) Determine the effect of macrophage activation on intra-cellular survival and multiplication of L. pneumophila; (2) Determine the role of specific cell-mediated immunity in activating macrophages to kill or inhibit the multiplication of L. pneumophila; (3) Determine the roles of humoral and cellular immunity in protecting guinea pigs from lethal challenge with L. pneumophila; (4) Determine the mechanisms by which activated macrophages kill L. pneumophila; (5) Determine the mechanisms by which L. pneumophila resists phagocyte microbicidal activities and survives intracellularly; (6) Determine the origin, identity, and role of the unique ribosome-like structures studding the vacuolar membrane surrounding intracellular L. pneumophila in monocytes; and (7) Determine the effect of antibiotics on the phagocyte-parasite relationship.